Osteoporosis is a common and progressive condition occurring in adults which results in a decrease in bone throughout the body. This loss includes the mineral portion of the bone, which is a calcium phosphate material called "hydroxyapatite", as well as the matrix, which is a protein called "collagen". Osteoporosis may begin in early adulthood and progress, inexorably, to middle age and old age with manifestations running the gamut of moderate to severe pain along with X-ray evidence of bone loss and/or deformation to eventual brittleness which we see evidenced, for example, in older people who so easily break a hip bone from a simple, and seemingly not dangerous, fall. It has been stated that osteoporosis is the most common cause of fractures in people over the age of 65.
While the causes of osteoporosis are not well understood and, in many cases quite obscure, it is believed that there is an imbalance between bone production and bone resorption (i.e., bone breakdown).
During the life of an animal, new bone is continuously being formed and old bone resorbed. In osteoporosis, resorption exceeds bone formation.
Present methods for treating osteoporosis are far from satisfactory. Such treatments include the administration of calcium salts, fluorides, calcitonin, estrogens, Vitamin D, and anabolic agents, among others. Anabolic agents and estrogen therapy have been the therapy of choice for osteoporosis in post-menopausal women. Such treatments appear to entail an increased risk of uterine and breast cancer. Other treatments still remain to be proven including the Physical Therapy approach.
Among the newer approaches to the treatment of osteoporosis has been the use of materials with hypocalcemic activity, i.e., lowering of the serum calcium, which is believed to be related to and indicative of a decrease in the rate of bone resorption. Calcitonin, mithramycin (an antibiotic) and certain phosphonates are representative hypocalcemic agents, but adverse effects and lack of effectiveness in bone-loss prevention associated with the use of such agents, make continued research necessary.
In recent U.S. Pat. Nos. 4,101,668 (issued Jul. 18, 1978), 4,125,621 (issued Nov. 14, 1978) and 4,185,108 (issued Jan. 22, 1980), all three having as inventors C. M. Samour and J. A. Vida, there are disclosed a wide variety of benzo-heterocyclic compounds for use as antiosteoporotic agents. Among the specific compounds described are thionaphthene-2-carboxylic acid, thionaphthene-3-carboxylic acid, thionaphthene-4-carboxylic acid, dibenzothiophene-4-carboxylic acid, thioxanthene-9-one-4-carboxylic acid and indole-2-carboxylic acid.
The compounds are compared to thyrocalcitonin (TCT), the latter, a bond-remodeling hormone which is capable of reducing bone resorption rates. In the patented disclosures, the effectiveness of any bone resorption modifying agent is determined by measuring the effect on the production of cyclic adenosine-3'5'-monophosphate (c-AMP) using the methods of Rodan et al, J.B.C. Vol 429, page 306, 1974; Rodan et al, Science, Vol. 189, page 467, 1975. In the comparison, the activity shown by the free acid compounds covered by the disclosure of the aforementioned patents ranges from slightly more than half as effective to twice as effective as TCT in stimulating the production of c-AMP.